Pulmonary arterial hypertension (PAH) is a rare disease associated with high morbidity and mortality. The purpose of this proposal is to develop a novel combined JAK1/JAK2 inhibitor or more selective JAK2 inhibitor for PAH that will be delivered by inhalation. The lead drug candidates will provide a treatment for the two key etiologic factors that lead to PAH: vasoconstriction and pathologic cellular proliferation. Because PAH involves the pulmonary arteriolar bed, direct delivery of the drug by inhalation will improve the therapeutic window: i.e., increase efficacy, and decrease systemic side effects. The approach will consist of the following steps: 1) Formulate the drug candidates for aerosolization and determine the respiratory deposition pattern of inhaled aerosol with SPECT gamma scintigraphy and three dimensional computed tomography. 2) Determine the inhaled and deposited mass of the drug candidates and pharmacokinetic distribution of the drug candidates. 3) Determine the efficacy and therapeutic window of lead drug candidates in 2 models of PAH. The results of this project will lead to formulation of one of the lead candidates for use in humans and IND enabling studies. This new treatment could reduce the morbidity and mortality of PAH and thereby benefit patients and society. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension is a devastating disease with a high morbidity and mortality. This project is relevant to public health because it will ultimately lead to a new treatment for pulmonary arterial hypertension.